15-Deoxy-16-hydroxy-16-vinyl and cyclopropyl substituted prostanoic acids and congeners

ABSTRACT

This disclosure describes novel 15-deoxy-16-hydroxy-16-substituted prostanoic acids and congeners thereof having utility as bronchodilators, as hypotensive agents and as agents for the control of excessive gastric secretion.

This application is a continuation-in-part of our application Ser. No.706,343 filed July 19, 1976 now U.S. Pat. No. 4,061,670.

BRIEF SUMMARY OF THE INVENTION

This invention relates to novel 15-deoxy-16-hydroxy-16-substitutedprostanoic acids and cogeners thereof, as well as to intermediates andmethods for their preparation.

The novel compounds of this invention embrace all the optical antipodes,racemic mixtures and diasteromeric mixtures corresponding to thefollowing general formula, the absolute configuration of which is thatof the natural mammalian prostaglandins.

The compounds of this invention may be represented by the followinggeneral formula and the mirror image thereof: ##STR1## wherein W isselected from the group comprising ##STR2## wherein R₁ is selected fromthe group comprising hydrogen and lower alkyl (C₁ -C₁₂); R₂ is an alkylor alkenylmethyl group (C₃ -C₇) optionally substituted with one or twoalkyl groups of one to three carbon atoms; R₃ is selected from the groupcomprising hydrogen, hydroxyl, alkanoyloxy (C₂ -C₆),triloweralkylsilyloxy, tetrahydropyran-2-yloxy and alkoxy (C₁ -C₃); R₄is selected from the group comprising hydrogen and alkanoyloxy (C₂ -C₆);T is the divalent radical ##STR3## wherein R₅ is selected from the groupcomprising vinyl, methylvinyl and cyclopropyl; the moiety C₁₃ -C₁₄ iseither trans-vinylene or ethylene; and Z is selected from the groupcomprising --(CH₂)₆, --CH₂ --CH═CH--(CH₂)_(n), (CH₂)_(n) --S--CH₂ and(CH₂)_(n) --O--CH₂ , [with the proviso that when Z is (CH₂)_(n) SCH₂,then R₃ must not be an oxy function, with the further proviso that whenZ is (CH₂)_(n) SCH₂, then the cyclopentanone ring may not contain adouble bond;] where n is an integer from 3 to 5; and when R₁ ishydrogen, the pharmaceutically acceptable salts thereof.

Useful pharmacologically acceptable salts of the above formula, where R₁is hydrogen, are those with pharmacologically acceptable metal cations,ammonium, amine cations or quaternary ammonium cations.

Preferred metal cations are those derived from the alkali metals, e.g.lithium, sodium and potassium, and from the alkaline earth metals, e.g.magnesium and calcium, although cationic forms of other metals, e.g.aluminum, zinc and iron, are within the scope of this invention.

Pharmacologically acceptable amine cations are those derived fromprimary, secondary or tertiary amines such as mono-, di- ortrimethylamine, ethylamine, dibutylamine, triisopropylamine,N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine,cyclopentylamine, dicyclohexylamine, mono- or dibenzylamine, α- orβ-phenylethylamine, ethylenediamine, diethylenetriamine, and aryliphaticamines containing up to and including 18 carbon atoms, as well asheterocyclic amines, e.g. piperidine, morpholine, pyrrolidine,piperazine and lower alkyl derivative thereof, e.g. 1-methylpiperidine,4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine,1,4-dimethylpiperazine, 2-methylpiperidine, and the like, as well asamines containing water-solubilizing or hydrophilic groups, e.g. mono-,di-, or triethanolamine, ethyldiethanolamine, N-butylethanolamine,2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol,2-amino-2-methyl-1-propanol, tris(hydroxy-methyl)aminomethane,N-phenylethanolamine, N-(p-tert-amylphenyl)diethanolamine, galactamine,N-methylglucamine, N-methylglucosamine, ephedrine, phenyleprine,epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammoniumcations are tetramethylammonium, tetraethylammonium,benzyltrimethylammonium, phenyltriethylammonium and the like.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are administered in various ways forvarious purposes, e.g., intravenously, intramuscularly, subcutaneously,orally, intravaginally, rectally, bucally, sublingually, topically andin the form of sterile implants for prolonged action.

For intravenous injection or infusion, sterile aqueous isotonicsolutions are preferred. For that purpose, it is preferred, because ofincreased water solubility, that R₁ be hydrogen or a pharmacologicallyacceptable cation. For subcutaneous or intramuscular injection sterilesolutions or suspensions of the acid, salt, or ester form in aqueous ornon-aqueous media are used. Tablets, capsules, and liquid preparationssuch as syrups, elixirs, and simple solutions, with the usualpharmaceutical carriers are used for oral or sublingual administration.For rectal or vaginal administration, suppositories prepared as known inthe art are used. For tissue implants, a sterile tablet or siliconerubber capsule or other object containing or impregnated with thesubstance is used. On certain occasions it may be advantageous toadminister the compounds of this invention as clathrate compounds withsubstances such as α-cyclodextrin.

The prostaglandins are a family of closely related compounds which havebeen obtained from various animal tissues and which stimulate smoothmuscle, lower arterial blood pressure, antagonize epinephrine-inducedmobilization of free fatty acids, and have other pharmacological andautopharmacological effects in mammals. See Bergstom, et al., J. Biol.Chem., 238, 3555 (1963) and Horton, Experientia, 21, 113 (1965) andreferences cited therein. All of the so called natural prostaglandinsare derivatives of prostanoic acid: ##STR4## The hydrogen atoms attachedto C-8 and C-12 are in transconfiguration. The natural prostaglandinsrepresent only one of the possible optical isomers. The compounds ofthis invention include all possible optical isomers and racemates.

The configuration of substituents on the prostaglandin molecule aredesigned to be in the α-configuration if they lie beneath the plane ofthe molecule as drawn above and are designated with a bond. Thosesubstituents which lie above the plane of the molecule as drawn aboveare designated β and are represented by a bond.

The novel compounds of this invention can be prepared by a novel1,4-conjugate-addition procedure involving treatment of the etherblocked cyclopentenone (15) with a lithio-cuprate reagent such as (13)prepared as illustrated in Flowsheet A, in which R₂, R₃, R₄, R₅, W and nare as hereinabove described. R₁ ' is lower alkyl (C₁ -C₁₂) or, triloweralkylsilyl, or tetrahydropyran-2-yl and R₃ ' is hydrogen,triloweralkylsilyloxy or tetrahydropyran-2-yloxy. ##STR5##

In accordance with the procedure as outlined in Flowsheet A, an aldehyde(1) is treated with propargylic magnesium halide to form thehomopropargylic alcohol, (2) which is converted to its trimethylsilylether in the usual manner. The silylated derivative is then treated withdisiamylborane (prepared in situ in tetrahydrofuran solution at ice bathtemperature from 2-methyl-2-butene, sodium borohydride and borontrifluoride ethereate) and then anhydrous trimethylamine oxide. Theresulting solution and an iodine solution in tetrahydrofuran are thenadded simultaneously to an aqueous solution of sodium hydroxide to givethe 1-iodo-4-trimethylsilyloxy-trans-1-alkene (3).

The trimethylsilyl protecting group is removed with mild acid and theresulting vinyl iodide alcohol is oxidized with pyridiniumchlorochromate to provide the 1-iodo-4-oxo-trans-1-alkene(4), which upontreatment with a Grignard reagent (R₅ MgX) provides the1-iodo-4-hydroxy-trans-1-alkene, which is silylated in the usual mannerto provide the silyl ether (8a).

A more preferred method for the preparation of the vinyllithiumintermediate (9) is also described in Flowsheet A. Treatment of therequisite carboxylic acid (5 or 5a) with the appropriate organolithiumreagent (R₂ Li or R₅ Li respectively) gives the corresponding ketone (6)which upon treatment with propargylic magnesium halide provides thehomopropargylic alcohol (7) which is converted to the trans vinylstannylderivative by sequential treatment with chlorotrimethylsilane andtri-n-butylstanyl hydride in the presence of azobisisobutyrylnitrile.Treatment of the vinylstannyl reagent (8b) with n-butylithium at atemperature of -10° to -78° C. generates the vinyllithium reagent (9).

Treatment of (8a) at low temperature, preferably -30° C. to -78° C. inan inert solvent, e.g. hexane, ether or toluene, with an alkyl lithium,e.g. n-butyl lithium or t-butyl lithium (2 equivalents) provides thetrans-1-alkenyl lithium reagent (9). In the case of the vinylstannyl(8b) n-butyllithium is preferred for the generation of the vinyl lithiumreagent.

For the preparation of the asymmetrical lithio cuprate (12) or the like,a solution of one molar equivalent of copper (I)-1-alkyne, preferablycopper (I)-1-pentyne in anhydrous tributylphosphine or HMPTA, preferablyone to five molar equivalents in ether is added to one molar equivalentof the aforementioned vinyl-lithium solution cooled to about -78° C.After about one hour at this temperature, a molar equivalent of therequisite cyclopentenone (15) is added. After several hours at -30° C.to -70° C. the reaction mixture is quenched with aqueous ammoniumchloride solution and the blocked product (16) is isolated in the usualmanner.

It is also possible to effect conjugate 1,4-addition with theasymmetrical lithio cuprate (14) derived from vinyl lithium (9) andcuprous thiophenoxide. A solution of vinyl lithium (9) in ether at -78°C. is reacted with an equimolar amount of a reagent prepared byadmixture, in ether at a temperature of 0° C. to -78° C., of equimolaramounts of cuprous thiophenoxide and copper (I) iodidetributylphosphonium complex. After about 30 minutes at this temperature,the lithio cuprate (14) is treated with the requisite cyclopentenone(15) as described hereinabove for the conjugate addition with 1-alkynyllithio cuprate (12).

For the preparation of the symmetrical lithio cuprate (13) one molarequivalent of copper (I) iodide tributylphosphine complex, dissolved inanhydrous ether, is added at about -78° C. to two molar equivalents ofthe aforementioned vinyl iodide (9) solution in hexanes, cooled to -78°C. After about one hour at this temperature, the lithio cuprate (13) istreated with the requisite cyclopentenone (15) as described hereinabovefor the conjugate addition with the 1-alkynyl lithio cuprate (12).

The procedures for conjugate addition involving organocopper reagentsare well known in the art, see for example C. J. Sih, et al., J. Amer.Chem. Soc., 97, 865 (1975).

In the cases where R₁ '=trimethylsilyloxy in cyclopentenone (15) theconjugate addition is performed at -78° C. to -40° C. The reaction isquenched by addition of an ether solution of acetic acid. Removal ofblocking groups is then carried out as described in the reference aboveto provide the product (16a) wherein R₁, R₂ are as hereinabove definedand R₃ " is hydrogen or hydroxyl.

All available evidence leads us to believe that the ##STR6## functionintroduced by the cuprate process occupies a position trans to the11-oxy function. Similarly, we are led to the conclusion that in theproduct (16) the two side-chains attached to C₈ and C₁₂ are trans toeach other. However, we are not certain of this configurationalrelationship in the product as it is obtained directly from the cuprateprocess. These products may have the side-chains in a trans- orcis-relationship or they may be a mixture containing both the trans- andcis-isomers. This is indicated in the nomenclature of the compoundsinvolved by the designation 8ε. In order to ensure a trans-relationshipin (16) these products can be submitted to conditions known in theliterature to equilibrate the cis-8-iso-PGE₁ to a mixture containingabout 90% of the trans product. These conditions involve treatment withpotassium acetate in aqueous methanol for 96 hours at room temperature.

The triloweralkylsilyloxy substituted lithio-cuprate reagents of type(12) and its iodo and trialkylstannyl percursors are novel and usefulcompounds which are also embraced by this invention. They may be definedby generic formulae (A) and (B). ##STR7## wherein W is iodine or trin-butylstannyl, R₃ and R₅ are as hereinabove defined, R₆ is hydrogen ortriloweralkylsilyl, T is thiopheneoxide, substituted thiopheneoxide, analkyne or the identical vinyl moiety.

The 13-dihydro derivatives can be prepared, as shown in Flowsheet A, bytreating cycloalkenones of formula (15) with Grignard reagent such as(10), in the usual manner in the presence of a catalyst such as thetributylphosphine-cuprous-iodide complex. The trimethylsilyl and otherblocking groups are then removed in the usual manner as describedhereinabove.

In accordance with Flowsheet B, when the 11-hydroxy derivatives (R₁=hydroxy) or the 11-oxy derivatives embraced by (17) are treated withdilute acid, or dilute base, it is possible to effect elimination andthe formation of the corresponding Δ¹⁰ derivatives (18) prostaglandinsof the A type. A preferred procedure involves treatment intetrahydrofuran:water (2:1) solvent with 0.5N in HCl for about 70 hoursat ambient temperatures or alternatively in methanol-water solvent (1:5)with 0.2 M potassium carbonate for 16 hours at ambient temperatures.Under acidic conditions, a tetrahydropyranyl or trialkylsilyl ester willundergo hydrolysis. ##STR8## In Flowsheet B, R₁, Z and C₁₃ -C₁₄ areashereinabove defined and R₈ is the moiety ##STR9## wherein R₂ and R₅are as hereinabove described.

The 11-oxy-9-keto derivatives of this invention can be converted to thecorresponding 9-hydroxy derivatives as described in Flowsheet C. If thisconversion is effected with sodium borohydride, the product is a mixtureof 9α- and 9β-hydroxy derivatives (19) and (20) respectively, as setforth in the following reaction scheme, wherein R₁, R₃, Z and C₁₃ -C₁₄are as herein above defined, and R₈ is the moiety ##STR10## wherein R₂and R₅ are as hereinabove defined. ##STR11##

When the reaction is carried out with lithium perhydro-9b-boraphenylylhydride [H. C. Brown and W. C. Dickason, J.A.C.S., 92, 709, (1970)] orlithium tris-(t-butyl)-borohydride [H. C. Brown and S. Krishnamurthy,ibid., 94, 7159 (1972)] the product is at least predominantly the9α-hydroxy derivative wherein the 9-hydroxy group is cis to the sidechain attached to C₈ and to the 11-oxy function, if present. Inaccordance with accepted convention, and α-substituent at the 8-, 9-,11- or 12-positions is behind the plane of the paper, whereas aβ-substituent at these positions is in front of the plane of paper. Thisis usually represented by a bond for an α-substitutent, a bond for aβ-substituent, and a bond where both are indicated.

In accordance with Flowsheet D, wherein R₉ is hydrogen or lower alkyl(C₁ -C₉) and Z, R₈ and C₁₃ -C₁₄ are as described hereinabove, treatmentof PGFα analogs with an oxidizing agent such as Jones reagent orpyridinium chlorochromate provides a selective oxidation of the11α-hydroxyl to provide compounds of the PGD structure such as (22).##STR12##

The carboxylic acids of this invention can be readily converted to thevarious alkyl esters of this invention by treatment in the usual mannerwith the appropriate diazoalkane. The preparation of diazoalkanes byvarious procedures are well described in the art. See for example C. D.Gutsche, Organic Reactions, VIII, 389 (1954). Certain of the esters ofthis invention can also be obtained directly by use of the appropriatecyclopentenone ester. The various esters can also be prepared by any ofseveral procedures well-known in the art via an acid chloride (priorblocking of free alcohol groups with appropriate blocking groups such astrialkylsilyl, tetrahydropyranyl and the like) or mixed anhydrides andtreatment of these intermediates with the appropriate alcohol. Mixedanhydrides can be obtained by treatment of the prostaglandin acid in asolvent such as dioxane at a temperature in the range of 0° to 15° C.with a molar equivalent of a tri-alkylamine, preferably triethylamine,tributylamine and the like, and then a molar equivalent of isobutylchlorocarbonate or the like. The resulting mixed anhydrides is thentreated with the appropriate alcohol to give the derivatized product.[For a pertinent literature analogy see Prostaglandins, 4, 738 (1973). ]

An alternative procedure involves treatment of the prostaglandin acidwith a molar equivalent of the trialkyl amine in an excess of theappropriate alcohol in an anhydrous solvent such as methylene chloride,a molar equivalent of p-toluenesulfonyl chloride is then added (ifnecessary, a second molar equivalent can be added) and after stirring atambient temperatures for about 15 minutes to one hour the product isworked-up in the usual manner. (For a pertinent literature analogy, seeU.S. Pat. No. 3,821,279. ) A third procedure involves the use ofdicyclohexylcarbodiimide in the usual manner; for a pertinent literatureanalogy see German Offen. 2,365,205; Chem. Abst., 81, 120098g (1974).

The esterified alcohol derivatives of this invention are also preparedin the usual manner by procedures well known in the art from theappropriate alkanoic acid anhydride or acid chloride.

When the compounds of this invention are prepared from racemic startingcompounds, two racemates are obtained. In appropriate instances theseracemates may be separated from each other by careful application of theusual chromatographic procedures. In the more difficult instances it maybe necessary to apply high pressure liquid chromatography includingrecycling techniques. [See G. Fallick, American Laboratory, 19-27(August 1973) as well as references cited therein. Additionalinformation concerning high speed liquid chromatography and theinstruments necessary for its application is available from WatersAssociate Inc., Maple Street, Milford, Mass. ]

In the following formulae Z is as hereinabove defined.

The 4-hydroxycyclopentenone racemates may be resolved into theircomponent enantiomers (23) and (24) wherein Z is as hereinabove definedby derivatizing the ketone function with a reagent having an opticallyactive center. The resulting diastereoisomeric mixture can then beseparated by fractional crystallization, or by chromatography, or byhigh speed liquid chromatography involving, if necessary, recyclingtechniques. Among the useful optically active ketone derivatizingreagents are 1-α-aminoxy-α-methylpentanoic acid hydrochloride (to give25), (R)-2-aminoxy-3,3-dimethylbutyric acid hydrochloride, and4-α-methylbenzyl semicarbazide. After separation of the diastereomericderivatives, reconstitution of the keto function provides the individual4-hydroxycyclopentenone enantiomers (23) and (24). A useful procedurefor the resolution of a 4-hydroxycyclopentenone racemate via an oximesuch as (25) is described in the art [R. Pappo, P. Collins and C. Jung,Tetrahedron Letters, 943 (1973)]. The resolution of thehydroxycyclopentenone (23) wherein Z is ##STR13## is described by Bruhnet al, Tetrahedron Letters, 235 (1976). ##STR14##

An alternative procedure for the preparation of the4(R)-hydroxycyclopentenone enantiomers such as (23) involves as a keystep the selective microbiological or chemical reduction of trione (26)to the 4(R)-hydroxycyclopentanedione (27). A wide variety ofmicroorganisms are capable of accomplishing this asymmetric reduction,one of the most useful being Dipodascus unincleatus.

Conversion of hydroxycyclopentanedione (27) to an enol ether or enolester, (28), E=alkyl, preferably isopropyl; aroyl such as benzoyl; orarylsulfonyl such as 2-mesitylenesulfonyl), is accomplished bytreatment, for example, with isopropyl iodide and a base such aspotassium carbonate in refluxing acetone for from 15 to 20 hours, orwith a base such as triethylamine and 0.95 equivalents of benzoylchloride or a slight excess of 2-mesitylenesulfonyl chloride, in anon-prototropic solvent at a temperature of about -10° C. to -15° C.Reduction of (28) with excess sodium bis(2-methoxyethoxy)aluminumhydride in a solvent such as tetrahydrofuran or toluene at lowtemperatures, such as -60° C. to -78° C., followed by mild acidhydrolysis (representative conditions: aqueous dilute hydrochloric acid,pH 2.5; or oxalic acid, sodium oxalate in chloroform) at ambienttemperatures from 1 to 3 hours provides the 4(R)-hydroxycyclopentenoneester (29). The ester (29) after blocking the hydroxy function asdescribed hereinabove, can be subjected to conjugate addition reactionsalso as described hereinabove. The conjugate addition product, afterdeblocking the 11- and 15-hydroxy groups, will then be a methyl esterwhich can be hydrolyzed to the corresponding carboxylic acid byenzymatic or microbiological procedures, for example with baker's yeastor by exposure to Rhizopus oryzae.

For a description of these procedures in the art see: C. J. Sih, et al.,J. A. C. S., 95, 1676 (1973); J. B. Heather, et al., TetrahedronLetters, 2213 (1973); R. Pappo and P. W. Collins, Tetrahedron Letters,2627 (1972); R. Pappo, P. Collins and C. Jung, Ann. N. Y. Acad. Sci.,180, 64 (1971); C. J. Sih, et al., J. A. C. S., 97, 865 (1975). For adescription of the baker's yeast procedure see C. J. Sih, et al., J. A.C. S., 94, 3643 (1972). ##STR15##

Procedures for the preparation of the requisite cyclopentanetriones (26)are well-established in the art and generally involve the treatment ofan ω-1 oxo long chain ester (30) with methyl or ethyl oxalate and a basesuch as sodium methoxide in methanol, followed by treatment with dilutehydrochloric acid in aqueous methanol to effect the dealkoxalylation ofthe intermediate (31). See J. Kutsube and M. Matsui, Agr. Biol. Chem.,33, 1078 (1969); P. Collins, C. J. Jung and R. Pappo, Israel Journal ofChemistry, 6, 839 (1968); R. Pappo, P. Collins and C. Jung, Ann. N. Y.Acad. Sci., 180, 64 (1971); C. J. Sih, et al., J. A. C. S., 95, 1676(1973) (see reference 7); and J. B. Heather, et al., TetrahedronLetters, 2313 (1973) for pertinent background literature. ##STR16##

The intermediate keto esters (30) may be prepared by a variety ofmethods known to the art. One useful procedure is outlined below andinvolves alkylation of ethyl acetoacetate sodium salt (32) [in the usualmanner with the appropriate side-chain precursor (33) X=Cl, Br, I,preferably Br or I] followed by decarbethoxylation and reesterification,all in the usual manner. ##STR17##

It is also possible to resolve the 4-hydroxycyclopentenone racemate (36)by microbiological means. Thus, treatment of the 4-O-alkanoyl or aroylderivatives (37) R₁₂ =aryl or alkyl) of racemate (36) (preferably the4-O-acetyl and 4-O-propionyl derivatives) with an appropriatemicroorganism preferably a Saccharomyces species, e.g., 1375-143,affords preferential de-O-acylation of the 4(R)-enantiomer to give (23),which is then separated from the unreacted 4-(S)-O-acyl enantiomer (38)by chromatographic procedures. After separation, mild hydrolysis of the4(S) derivative (38) provides the 4(S)-hydroxycyclopentenone (24) [SeeN. J. Marscheck and M. Miyano, Biochimica et Biophysica Acta, 316, 363(1973) for related examples.] ##STR18##

It is also possible to prepare the individual 4-hydroxycyclopentenones(23) and (24) directly by selective microbial hydroxylations of thecorresponding 4-unsubstituted cyclopentenone (39). For example, withAspergillus niger ATCC 9142; a selective 4(R)-hydroxylation of (39)[Z=(CH₂)₆ ] has been reported; for a literature example, see S.Kurozumi, T. Tora and S. Ishimoto, Tetrahedron Letters, 4959 (1973).Other organisms can also accomplish this hydroxylation. ##STR19##

An alternate resolution procedure involves derivatization of the alcoholfunction of the racemic hydroxycyclopentenone to give ester-acidderivatives such as (40) wherein R₃ " is hydrogen or an alkyl group, n'is zero or two and Z is as hereinabove defined. ##STR20##

Such derivatives may be obtained from the corresponding freehydroxycyclopentenone by treatment in the usual manner with oxalylchloride, succinyl chloride, succinic anhydride and thelike. Treatmentof the resulting acid or diacid (R₃ "=hydrogen) with optically activeamines e.g., 1-(-)-α-methylbenzylamine, d-(+)-α-methylbenzylamine,brucine, dehydroabietylamine, strychnine, quinine, cinchonine,quinidine, ephedrine, (+)-α-amino-1-butanol and the like, and fractionalrecrystallization of the resulting diastereomeric mixtures, followed bycleavage of the 4-oxy ester function in each of the individuallyisolated diastereomers provides the individual 4(S)- and4(R)-hydroxycyclopentenone enantiomers (23) and (24) or their respectiveesters. Cleavage of the oxalate acid ester (40 n=0) can be accomplishedby treatment with lead tetraacetate in pyridine solution. For an exampleof a similar use of oxalate acid-esters see J. G. Molotkovsky and L. D.Bergelson, Tetrahedron Letters, 4791 (No. 50, 1971); for an example ofthe use of succinate acid-ester see B. Goffinet, Ger. Offen. 2,263,880;Chem. Abstracts, 79, 78215_(z) (1973).

Additional procedures, well-understood in the literature, for effectingthe resolution of racemic prostenoic acids and esters of this inventionare described below.

In these procedures a 9-oxo-11α,16(S)-16-vinyldihydroxy-5-cis,13-trans-prostadienoic acid and its 9α-hydroxy derivative are used forillustrative purposes, it being understood, however, that the proceduresare general and have applicability to the other products of thisinvention, particularly to those derivatives wherein the 11-position isnot substituted with an oxy function.

Conversion of a 9α-hydroxy racemate (the component enantiomers areillustrated by (41) and (42) wherein the C₁₁ and C₁₆ hydroxy functionsare preferentially blocked as tetrahydropyranyl or trialkylsilyl ethersand conversion of the diacid (e.g., 41) to a bis salt (e.g., 43) with anoptically active amine (e.g., 1-(-)-α-methylbenzylamine,D-(+)-α-methylbenzylamine, brucine, dehydroaebietylamine, styrychnine,quinine, cinchonine, cinchonindine, quinidine, ephedrine,deoxyephedrine, amphetamine, (+)-2-amino-1-butanol,(-)-2-amino-1-butanol and the like). The resulting diastereomers arethen separated by fractional crystallization and the individualcomponents are then converted by acidification and saponification to theindividual optically active parent 9α-hydroxy enantiomers (41) and (42)oxidation of which after preferential blocking of the C₁₁ and C₁₆hydroxy functions with tetrahydropyranyl or trialkylsilyl groups,provides the corresponding individual 9-oxo enantiomers (45) and (46)(For an appropriate literature procedure see E. W. Yankee, C. H. Lin andJ. Fried, Journ. Chem. Soc., 1972, 1120). ##STR21##

Another procedure involves conversion of the 9α-hydroxy racemate(as theprostenoic acid ester and with the C₁₁ and C₁₆ alcohol functionspreferentially blocked as tetrahydropyranyl or trialkylsilyl ethers) tothe diastereomeric carbamates with an optically active isocyanate, e.g.,(+)-1-phenylethylisocyanate or (-)-1-phenylethylisocyanate, followed bydeblocking. Separation of the diastereomers, for example (47) and (48)can be accomplished by fractional crystallization or by the usualchromatographic procedures, or if necessary by high speed liquidchromatography involving, if necessary, recycling techniques.Base-treatment of the individual diastereomeric carbamates affords theindividual diastereomeric alcohols, for example (41) and (42). ##STR22##

It is also possible to effect resolution of a 9α-hydroxy racemate,preferably as the prostenoate esters, by esterification of the9α-hydroxy function (prior preferential blocking of C₁₁ and C₁₆ hydroxyfunctions as tetrahydropyranyl or trialkylsilyl ethers) with anoptically active acid, via its acid chloride followed by deblocking theC₁₁ and C₁₆ alcohol groups. Suitable optically active acids includeω-camphoric acid, menthoxyacetic acid, 3α-acetoxy-Δ⁵ -etianic acid,(-)-α-methoxy-α-trifluoromethylphenylacetic acid and (+)-α-methoxy-α-trifluoromethylphenylacetic acid, and the like. Theresulting diastereomeric esters, are then separated by fractionalcrystallization or by chromatographic techniques including, ifnecessary, the use of high speed liquid chromatography. Saponificationof the individual diastereomers then provides the individual9α-hydroxyprostenoic acid enantiomers (49) and (50). ##STR23##

Another resolution procedure, less useful than the methods describedabove based on the 9α-hydroxy derivative but particularly applicable to11-unsubstituted compounds of this invention, involves derivatization ofthe keto function of a racemic 9-oxoprostenoic acid or ester illustratedby (51) and (52) with the usual type of ketone derivatizing agentbearing an optically active center. The resulting mixture ofdiastereomeric derivatives can then be separated by fractionalcrystallization or by chromatography or, if necessary, by high speedliquid chromatography. The individual diastereomeric keto derivatives,for example (51) and (52) are then convertable to the individual 9-oxoenantiomers (45) and (46) by any of the usual cleavage techniques,provided that they are sufficiently mild so as not to disturb thesensitive 11-hydroxy-9-keto system. (This latter point is not a problemwith 11-unsubstituted derivatives.) Ketone reduction of the9-oxo-enantiomer as described hereinabove then provides thecorresponding 9α-hydroxy or 9β-hydroxy enantiomer. Among the opticallyactive reagents useful for ketone derivatization are1-α-aminoxy-α-methylpentanoic acid hydrochloride [E. Testa, et al.,Helv. Chimica Acta, 47 (3), 766 (1973)],methylhydrazine, and4-α-methylbenzylsemicarbazide. A useful procedure for the cleavage ofoximes such as (51) and (52) involves treatment of the oxime at about60° C. for about 4 hours in 1:2 aqueous-tetrahydrofuran buffered withammonium acetate and containing titanium trichloride. ##STR24##

Other useful ketone derivatizing agents are optically active1,2-glycols, e.g., D(-)-2,3-butanediol, or 1,2-dithiols, e.g.,L(+)-2,3-butanedithiol. These are used to convert the 9-oxo derivativeto 9,9-alkylenedioxa or 9,9-alkylenedithia derivatives, separation ofdiastereomers by chromatographic procedures followed by regeneration ofthe individual 9-oxo diastereomer by ketal cleavage all by procedureswell-known in the art. Both ketalization and deketalization would haveto be accomplished by procedures which would not disrupt the11-oxo-9-keto system, which of course, is not a problem in the11-unsubstituted series.

The novel compounds of the present invention have potential utility ashypotensive agents, anti-ulcer agents, agents for the treatment ofgastric hypersecretion and gastric erosion, agents to provide protectionagainst the ulcerogenic and other gastric difficulties associated withthe use of various non-steroidal antiinflammatory agents (e.g.,indomethacin, aspirin, and phenylbutazone), bronchodilators,antiinflammatory agents, abortifacients, agents for the induction oflabor, agents for the induction of menses, fertility-controlling agentsoestrus regulators for the use in animal husbandry with cattle and otherdomestic animals and central nervous system regulatory agents. Certainof the novel compounds of this invention possess utility asintermediates for the preparation of other of the novel compounds ofthis invention.

The ring system of certain of the novel compounds of this inventionallow them to be characterized as follows: ##STR25##

The novel compounds of this invention possess the pharmacologicalactivity described below as associated with the appropriateabove-described prostaglandin type.

The known PGE, PGF.sub.α, PGF.sub.β, PGA and PGD compounds are allpotent in causing multiple biological responses even at low doses. Forexample, PGE₁ and PGE₂ are extremely potent in causing vasodepressionand smooth muscle stimulation, and also are potent as antilipolyticagents. Moreover, for many applications, these known prostaglandins havean inconveniently short duration of biological activity. In strikingcontrast, the novel prostaglandin analogs of this invention aresubstantially more specific with regard to potency in causingprostaglandin-like biological responses, and/or having a substantially,longer duration of biological activity. Therefore, each of these novelprostaglandin analogs is surprisingly and unexpectedly more useful thanone of the corresponding above-mentioned known prostaglandins for atleast one of the pharmacological purposes indicated below for thelatter, either because it has a different and narrower spectrum ofbiological activity than the known prostaglandins, and therefore is morespecific in its activity and causes smaller and fewer undesired sideeffects than the known prostaglandins, or because of its prolongedactivity, fewer and smaller doses of the novel prostaglandin analog canfrequently be used to attain the desired result.

The 11-deoxy-PGE, PGF.sub.α and PGF.sub.β compounds are additionallyselective in that they are at most relatively very weak stimulants ofsmooth muscle. The 11-deoxy PGE compounds have a further advantage inthat they are much more stable and have a longer "shelf-life" than thecorresponding 11-hydroxy derivatives as described more fullyhereinbelow.

Another advantage of the novel compounds of this invention, comparedwith the known prostaglandins, is that these novel compounds areadministered effectively, orally, sublingually, intravaginally,buccally, or rectally, in addition to the usual intravenous,intramuscular, or subcutaneous injection or infusion methods indicatedabove for the uses of the known prostaglandins. These qualities areadvantageous because they facilitate maintaining uniform levels of thesecompounds in the body with fewer, shorter, or smaller doses, and makepossible self-administration by the patient.

PGE₁, PGE₂, PGE₃ and dihydro-PGE₁, and the corresponding PGF.sub.α,PGF.sub.β, and PGA, compounds, and their esters and pharmacologicallyacceptable salts, are extremely potent in causing various biologicalresponses. For that reason, these compounds are useful forpharmacological purposes. See, for example, Bergstron, et al.,Pharmacol. Rev., 20, 1 (1968), and references cited therein. A few ofthose biological responses are systemic arterial blood pressure loweringin the case of the PGE, PGF.sub.β, and PGA compounds as measured, forexample, in anesthetized (phenobarbital sodium) pentolinium-treated ratswith indwelling aortic and right heart cannulas; pressor activity,similarly measured, for the PGF.sub.α compounds; stimulation of smoothmuscle as shown, for example, by tests on strips of guinea pig ileum,rabbit duodenum, or gerbil colon; potentiation of other smooth musclestimulants; antilipolytic activity as shown by antagonism ofepinephrine-induced mobilization of free fatty acids or inhibition ofthe spontaneous release of glycerol from isolated rat fat pads;inhibition of gastric secretion in the case of the PGE and PGA compoundsas shown in dogs with secretion stimulated by food or histamineinfusion; activity on the central nervous system; decrease of bloodplatelet adhesiveness in the case of PGE, as shown by platelet-to-glassadhesiveness, and inhibition of blood platelet aggregation and thrombusformation induced by various physical stimuli, e.g., arterial injury,and various biochemical stimuli, e.g., ADP, ATP, serotonin, thrombin,and collagen; and in the case of the PGE compounds, stimulation ofepidermal proliferation and keratinization as shown when applied inculture to embryonic chick and rat skin segments.

Because of these biological responses, these known prostaglandins areuseful to study, prevent, control, or alleviate a wide variety ofdisease and undesirable physiological conditions in birds and mammals,including humans, useful domestic animals, pets, and zoologicalspecimens, and in laboratory animals, for example, mice, rats, rabbits,and monkeys.

For example, these compounds, and especially the PGE compounds, areuseful in mammals, including man, as nasal decongestants. For thispurpose, the compounds are used in a dose range of about 10 μg to about10 mg per ml of a pharmacologically suitable liquid vehicle or as anaerosol spray, both for topical application.

The PGE and PGA compounds are useful in mammals, including man andcertain useful animals, e.g., dogs and pigs, to reduce and controlexcessive gastric secretion, thereby reducing or avoiding gastricerosion or gastrointestinal ulcer formation, and accelerating thehealing of such ulcers already present in the gastrointestinal tract.For this purpose, the compounds are injected or infused intravenously,subcutaneously, or intramuscularly in an infusion dose range of about0.1 g to about 500 μg per kg of body weight per minute, or in a totaldaily dose by injection or infusion in the range of about 0.1 mg toabout 20 mg per kg of body weight per day, the exact dose depending onthe age, weight, and condition of the patient or animal, and on thefrequency and route of administration. These compounds may also beuseful in conjunction with various non-steroidal anti-inflammatoryagents, such as aspirin, phenylbutazone, indomethacin and the like, tominimize the well-known ulcerogenic effects of the latter.

The PGE₁ and PGD₂ compounds are useful whenever it is desired to inhibitplatelet aggregation, to reduce the adhesive character of platelets, andto remove or prevent the formation of thrombi in mammals, including man,rabbits, and rats. For example, these compounds are useful in treatmentand prevention of myocardial infarcts, to treat and preventpost-operative thrombosis. For these purposes, these compounds areadministered systemically, e.g., intravenously, subcutaneously,intramuscularly, and in the form of sterile implants for prolongedaction. For rapid response, especially in emergency situations, theintravenous route of administration is preferred. Doses in the range ofabout 0.005 mg to about 20 mg per kg of body weight per day are used,the exact dose depending on the age, weight, and condition of thepatient or animal, and on the frequency and route of administration.

11α-Hydroxy-PGE compounds are extremely potent in causing stimulation ofsmooth muscle, and are also highly active in potentiating other knownsmooth muscle stimulators, for example, oxytocic agents, e.g., oxytocin,and the various ergot alkaloids including derivatives and analogsthereof. Therefore PGE₂, for example, is useful in place of or incombination with less than usual amounts of these known smooth musclestimulators, for example to relieve the symptoms of paralytic ileus, orto control or prevent uterine bleeding after abortion or delivery, toaid in expulsion of the placenta, and during the puerperium. For thelatter purpose, the PGE compound is administered by intravenous infusionimmediately after abortion or delivery at a dose in the range about 0.01μg to about 50 μg per kg of body weight per minute until the desiredeffect is obtained. Subsequent doses are given by intravenous,subcutaneous, or intramuscular injection or infusion during puerperiumin the range of 0.01 mg to 2 mg per kg of body weight per day, the exactdose depending on the age, weight, and condition of the patient oranimal.

The PGE, PGF.sub.β and PGA compounds are useful as hypotensive agents toreduce blood pressure in mammals including man. For this purpose, thecompounds are administered by intravenous infusion at the rate about0.01 μg to about 50 μg per kg of body weight per minute, or in a singleor multiple doses of about 25 μg to 2500 μg per kg of body weight totalper day.

The PGE, PGF.sub.α, and PGF.sub.β compounds are useful in place ofoxytocin to induce labor in pregnant female animals, including man,cows, sheep, pigs, at or near term or in pregnant animals withintrauterine death of the fetus from about 20 weeks to term. For thispurpose, the compound is infused intravenously at a dose 0.01 μg to 50μg per kg of body weight per minute until or near the termination of thesecond stage of labor, i.e., expulsion of the fetus. These compounds areespecially useful when the female is one or more weeks postmature andnatural labor has not started, or 12 to 60 hours after the membraneshave ruptured and natural labor has not yet started.

The PGE, PGFα, and PGFβ compounds are useful for controlling thereproductive cycle in ovulating female mammals, including humans andother animals. For that purpose, PGF₂ α, for example, is administeredsystemically at a dose level in the range of 0.01 mg to about 20 mg perkg of body weight, advantageously during a span of time startingapproximately at the time of ovulation and ending approximately at thetime of menses or just prior to menses. Additionally, expulsion of anembryo or fetus is accomplished by similar administration of thecompound during the first third or the second third of the normalmammalian gestation period. Accordingly, they are useful asabortifacients. They are also useful for induction of menses duringapproximately the first two weeks of a missed menstrual period andaccordingly are useful as contraceptive anti-fertility agents.

The PGA compounds and derivatives and salts thereof increase the flow ofblood in the mammalian kidney, thereby increasing volume and electrolytecontent of the urine. For that reason, PGA compounds are useful inmanaging cases of renal disfunction, especially in cases of severeimpaired renal blood flow, for example, the hepatorena syndrom and earlykidney transplant rejection. In case of excessive or inappropriate ADHantidiuretic hormone vasopressin secretion, the diuretic effect of thesecompounds is even greater. In anephretic states, the vasopressin actionof these compounds is especially useful. For that reason, thesecompounds are useful to promote and accelerate healing of skin which hasbeen damaged, for example, by burns, wounds, and abrasions, and aftersurgery. These compounds are also useful to promote and accelerateadherence and growth of skin autografts, especially small, deep (Davis)grafts which are intended to cover skinless areas by subsequent outwardgrowth rather than initially, and to retard rejection of homografts.

For these purposes, these compounds are preferably administeredtopically at or near the site where cell growth and keratin formation isdesired, advantageously as an aerosol liquid or micronized powder spray,as an isotonic aqueous solution in the case of wet dressings, or as alotion, cream, or ointment in combination with the usualpharmaceutically acceptable diluents. In some instances, for example,when there is substantial fluid loss as in the case of extensive burnsor skin loss due to other causes, systemic administration isadvantageous, for example, by intravenous injection or infusion,separate or in combination with the usual infusions of blood, plasma, orsubstituents thereof. Alternative routes of administration aresubcutaneous or intramuscular near the site, oral, sublingual, buccal,rectal, or vaginal. The exact dose depends on such factors as the routeof administration, and the age, weight, and condition of the subject. Toillustrate a wet dressing for topical application to second and/or thirddegree burns of skin area 5 to 25 square centimeters wouldadvantageously involve use of an isotonic aqueous solution containing 2to 2000 μg/ml of the PGE compound. Especially for topical use, theseprostaglandins are useful in combination with antibiotics, for example,gentamycin, neomycin, polymyxin B, bacitracin, spectinomycin, andoxytetracycline, with other antibacterials, for example, mafenidehydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone, andwith corticoid steroids, for example hydrocortisone, prednisolone,methylprednisolone, and fluoroprednisoline, each of those being used incombination at the usual concentrations suitable for its use alone.

The novel compounds of this invention induce the biological responsesdescribed hereinabove as associated with its particular prostaglandintype. These novel compounds are accordingly used for the above-describedcorresponding purposes.

The novel PGE, PGFβ and PGA compounds of this invention are also usefulas bronchodialtors for the treatment of asthma and chronic bronchitis.As such they may be conveniently administered by inhalation of aerosolsprays prepared in a dose range of about 10 μg to about 10 mg/ml of apharmacologically suitable liquid vehicle. Relative to the naturalprostaglandins, the PGE compounds in particular have the significantadvantage of inducing prolonged effects.

The invention will be described in greater detail in conjunction withthe following specific examples.

EXAMPLE 1 Preparation of 4-Trimethylsiloxy-1-octyne

To a cold solution of 166 g of 4-hydroxy-1-octyne [Prostaglandins, 10,289 (1975)], and 240 g of imidazole in one liter of dimethylformamide isadded dropwise 202 g of chlorotrimethylsilane. The mixture is allowed tostand at room temperature for 2 to 3 days. The mixture is partitionedwith water and hexane. The hexane layer is washed with brine, dried overmagnesium sulfate, and concentrated. Distillation of the residue gives acolorless liquid, b.p. 38° (0.2 mm).

EXAMPLE 2 Preparation of 1-Iodo-4-trimethylsiloxy-trans-1-octene

To a stirred solution of 0.20 moles of freshly preparedbis-(3-methyl-2-butyl)borane in 300 ml of tetrahydrofuran at 0°-5° C. isadded dropwise a solution of 19.8 g of 4-trimethylsiloxy-1-octyne in 30ml of tetrahydrofuran. The resulting mixture is stirred at ambienttemperature for several hours, cooled in an ice bath, and treated with53 g of trimethylamine oxide. The mixture is stirred several hours at25°-40° C. and then poured into 2 liters of 15% sodium hydroxide. Theresulting mixture is treated immediately with a solution of 140 g ofiodine in 300 ml of tetrahydrofuran. After 0.5 hour the organic phase isseparated and the aqueous phase is extracted with ether. The combinedorganic layers are washed with water, sodium thiosulfate solution, andbrine; dried over magnesium sulfate; and concentrated to give an oil,pmr spectrum (CDCl₃): 6.2 (d, ICH═) and 6.7 (quintuplet, ═CH--).

EXAMPLE 3 Preparation of 4-Hydroxy-1-iodo-trans-1-octene

A 23 g portion of 1-iodo-4-trimethylsiloxy-trans-1-octene is dissolvedin a mixture of 200 ml of glacial acetic acid, 100 ml oftetrahydrofuran, and 50 ml of water. After solution occurs, toluene isadded and the mixture is evaporated. The resulting oil ischromatographed on silica gel with hexane progressively enriched inbenzene followed by acetone to give 16 g of an oil, pmr spectrum(CDCl₃): 3.69 (m, CHOH) and 2.3 (s, OH).

EXAMPLE 4 Preparation of 4-Oxo-1-iodo-trans-1-octene

To a stirred suspension of 6.15 g of pyridinium chlorochromate(Tetrahedron Letters, 1975, 2647) in 20 ml of methylene chloride isadded 450 mg of sodium acetate. After 5 minutes a solution of 3.64 g of4-hydroxy-1-iodo-trans-1-octene in 15 ml of methylene chloride is addedin one portion. The dark mixture is stirred at room temperature for 75minutes, diluted with 50 ml of ether, and decanted. The solid sludge iswashed repeatedly with ether and decanted. The combined solutions arepercolated through Florisil. The solution is concentrated to give anorange liqud, pmr spectrum (CDCl₃): 3.20 (d, j=7 cps, ═CHCH₂ CO).

EXAMPLE 5 Preparation of 4-Hydroxy-4-vinyl-1-iodo-trans-1-octene

To a stirred solution of 7.8 ml of vinyl magnesium chloride (2.3 M intetrahydrofuran), at -25° C. is added a solution of 3.55 g of4-oxo-1-iodo-trans-1-octene in 20 ml of tetrahydrofuran during 15minutes. After the addition, the solution is stirred at -20° C. to -15°C. for 30 minutes. The reaction is quenched with a mixture of hexane andice. The aqueous phase is separated and extracted with additionalhexane. The combined hexane extracts are washed successively with waterand brine. The solution is dried over magnesium sulfate andconcentrated. The residue is subjected to dry column chromatography onsilica gel with benzene as developing solvent to give a liquid, pmrspectrum (CDCl3): 5.2 (m, terminal CH₂), 5.83 (q, CH═CH₂), 6.13 (d,ICH═), and 6.52 (m, ICM═CH).

EXAMPLE 6 Preparation of 4-Trimethylsiloxy-4-vinyl-1-iodo-trans-1-octene

To a stirred solution of 456 mg of4-hydroxy-4-vinyl-1-iodo-trans-1-octene and 320 mg of imidazole in 1.0ml of dimethylformamide is added 0.23 ml of chlorotrimethylsilane during3 minutes. The mixture is stirred at room temperature for 22 hours andpartitioned with a mixture of cold hexane and water. The hexane layer iswashed repeatedly with water and then brine, dried over magnesiumsulfate, and concentrated to give an oil, pmr spectrum (CDCl₃): 0.13 (s,trimethylsiloxy group) and 2.32 (d, ═CHCH₂).

EXAMPLE 7 Preparation of9-Oxo-11α,16-dihydroxy-16-vinyl-13-trans-prostenoic Acid

To a stirred solution of 555 mg of4-trimethylsiloxy-4-vinyl-1-iodo-trans-1-octene in 2 ml of ether isadded a solution of t-butyllithium in pentane (1.6 M) during 10 minutesat -78° C. The solution is stirred at -78° C. for 1.5 hours and at -50°C. for 30 minutes to provide the 1-lithio-trans-alkene.

In a separate flask a mixture of 0.21 g of 1-copper-(I)-1-pentyne, 0.70ml of hexamethylphosphorous triamide, and 2 ml of ether is stirred untila clear solution is obtained. This solution is added during 10 minutesto the stirred 1-lithio-trans-alkene solution at -78° C. The solution isstirred for 2 hours at -78° C. and then treated with a solution of 580mg of4-(trimethylsiloxy)-2-(6-carbotrimethylsiloxyhexyl)cyclopent-2-en-1-onein 3 ml of ether during 10 minutes. After 10 minutes at -78° C. thesolution is stirred at -40° C. to -50° C. for one hour and at -35° C. to-30° C. for one hour. The solution is cooled to -50° C., poured into 100ml of saturated ammonium chloride solution, and diluted with ether. Theorganic phase is separated, washed successively with water and dilutehydrochloric acid, and filtered through diatomaceous earth. The filtrateis washed successively with water and brine and dried over magnesiumsulfate. Evaporation of solvent affords the crude bis-trimethylsilylether as an oil.

This oil is treated with a solution prepared from 10 ml of glacialacetic acid, 5 ml of tetrahydrofuran, and 2.5 ml of water. The mixtureis stirred at room temperature for 30 minutes and diluted with 50 ml oftoluene. After concentration at 33° C. in vacuo, the residue issubjected to chromatography on silica gel with 1% acetic acid in ethylacetate to provide an oil, pmr spectrm (CDCl₃): 4.08 (q, 11β-H), 5.1 (m,terminal CH₂), 5.57 (m, trans-CH═CH), and 5.89 (m, (CH═CH₂).

EXAMPLE 8 Preparation of n-butyl cyclopropyl ketone

To a vigorously-stirred solution of 31.0 g of cyclopropanecarboxylicacid in 330 ml of ether is added a solution of n-butyllithium (748mmoles) in ca. 750 ml. of 2:1 ether-hexane during 1 hour at 5°-10° C.The resulting suspension is diluted with 300 ml of ether and stirred atroom temperature for 2 hours and at reflux for 2 hours. The mixture iscooled and poured into several portions of 1:1 ice--4 N hydrochloricacid. The ethereal phases are combined and washed with brine, sodiumcarbonate solution, and brine. The extract is dried over magnesiumsulfate and concentrated. The residue is distilled to provide a liquid,b.p. 102°-104° C. (80 mm), pmr spectrum (CDCl₃): δ 2.55 (triplet,--CH₂CO--).

EXAMPLE 9 Preparation of 4-Cyclopropyl-4-hydroxy-1-octyne

To a stirred, refluxing suspension of amalgam prepared from 6.2 g ofmagnesium and 50 mg of mercuric chloride suspended in 60 ml of ether isadded a solution of a mixture of 30.4 g of n-butyl cyclopropyl ketone(Example 8) and 29.8 g of propargyl bromide in 65 ml of ether during 60minutes. After reaction at reflux temperature for an additional 30minutes, the mixture is cooled to 0° and treated with 35 ml of saturatedammonium chloride. The mixture is diluted with ether and filteredthrough Celite. The filtrate is washed with brine, dried over potassiumcarbonate, and concentrated. The residue is distilled to provide aliquid, b.p. 93°-94° C. (12 mm), pmr spectrums (C D Cl₃): δ 0.43(cyclopropyl hydrogens), 2.07 (triplet, HC.tbd.C), and 2.44 (doublet,C.tbd.CCH₂).

EXAMPLE 10 Preparation of 4-Cyclopropyl-4-trimethylsiloxy-1-octyne

To a stirred solution of 27.8 g. of 4-cyclopropyl-4-hydroxy-1-octyne(Example 9) and 33.3 g. of imidazole in 130 ml of dimethylformamide at5° C. is added 24 ml. of chlorotrimethylsilane during 5 minutes. Thesolution is stirred at ambient temperature for 17 hours and thenpartitioned with 600 ml of hexane and 250 ml of ice-water. The hexanephase is separated and washed successively with water and brine. Thesolution is dried over magnesium sulfate and evaporated to give aliquid, p.m.r. spectrum (C D Cl₃): δ 0.12 (singlet, trimethylsiloxygroup), 2.02 (triplet, HC.tbd.C), and 2.45 (doublet, C.tbd.CH₂).

EXAMPLE 11 Preparation of4-Cyclopropyl-4-trimethylsiloxy-1-(tri-n-butylstannyl)-trans-1-octene

A stirred mixture of 23.8 g of 4-cyclopropyl-4-trimethylsiloxy-1-octyne(Example 10), 28 ml of tri-n-butyltin hydride, and 50 mg ofazobisisobutyronitrile under nitrogen is heated to 85° C. After theresulting exothermic reaction subsides the mixture is heated at 130° C.for 1 hour. The crude product is evaporatively distilled to give aliquid, p.m.r. spectrum (C D Cl₃): δ 0.10 (trimethylsiloxy group), 2.33(doublet, ═CHCH₂), and 6.02 (vinyl hydrogens).

EXAMPLES 12-13

In the manner of Example 8 the following cyclopropyl alkyl ketones ofTable 1 are prepared by reaction of the appropriate alkyllithium withcyclopropanecarboxylic acid.

                  Table 1                                                         ______________________________________                                                              Product Cyclopropyl Alkyl                               Example  Alkyllithium Ketone                                                  ______________________________________                                        12       n-propyllithium                                                                            cyclopropyl-n-propyl ketone                             13       n-amyllithium                                                                              n-amyl cyclopropyl ketone                               14       n-hexyllithium                                                                             cyclopropyl n-hexyl ketone                              ______________________________________                                    

EXAMPLES 15-18

The following vinyl ketones of Table 2 below are prepared by reaction ofvinyllithium with the requisite carboxylic acids of the table accordingto a procedure well-known in the art [J. C. Floyd, Tetrahedron Letters,2877 (1974)].

                  Table 2                                                         ______________________________________                                                                Product Alkyl Vinyl                                   Example   Carboxylic Acid                                                                             Ketone                                                ______________________________________                                        15        n-butyric acid                                                                              n-propyl vinyl ketone                                 16        n-valeric acid                                                                              n-butyl vinyl ketone                                  17        n-hexanoic acid                                                                             n-amyl vinyl ketone                                   18        n-heptanoic acid                                                                            n-hexyl vinyl ketone                                  ______________________________________                                    

EXAMPLES 18a-20

In the manner of Example 9 the following 4-substituted-1-alkyn-4-ols areprepared by reaction of propargyl magnesium bromide with the ketones ofTable 3 below.

                  Table 3                                                         ______________________________________                                                 Starting Ketones                                                                            Product 4-Substitut-                                   Example  of Example    ed-1-alkyn-4-ol                                        ______________________________________                                         18a     12            4-cyclopropyl-4-hydroxy-                                                      1-heptyne                                               18b     13            4-cyclopropyl-4-hydroxy-                                                      1-nonyne                                                18c     14            4-cyclopropyl-4-hydroxy-                                                      1-decyne                                                18d     15            4-hydroxy-4-vinyl-1-                                                          heptyne                                                19       17            4-hydroxy-4-vinyl-1-                                                          nonyne                                                 20       18            4-hydroxy-4-vinyl-1-                                                          1-decyne                                               ______________________________________                                    

EXAMPLES 21-25

In the manner of Example 10 the following 4-substituted-1-alkyn-4-ols ofTable 4 below are converted to their corresponding trimethylsilylethers.

                  Table 4                                                         ______________________________________                                                  1-Alkyn-4-ol of                                                                            Product 4-Trimethylsiloxy-                             Example   Example      1-alkyne                                               ______________________________________                                        21         18a         4-cyclopropyl-4-trimethyl-                                                    siloxy-1-heptyne                                       22         18b         4-cyclopropyl-4-trimethyl-                                                    siloxy-1-nonyne                                        23         18c         4-cyclopropyl-4-trimethyl-                                                    siloxy-1-decyne                                        24         18d         4-trimethylsiloxy-4-vinyl-                                                    1-heptyne                                              25        19           4-trimethylsiloxy-4-vinyl-                                                    1-nonyne                                               26        20           4-trimethylsiloxy-4-vinyl-                                                    1-decyne                                               ______________________________________                                    

EXAMPLES 27-32

In the manner of Example 11 the following1-(tri-n-butylstannyl)-4-substituted-4-trimethylsiloxy-trans-1-alkenesare prepared by reaction of tri-n-butyltin hydride with the precursor1-alkynes of Table 5 below.

                  Table 5                                                         ______________________________________                                                  Starting 1-Alkyns                                                                           Product 1-(tri-n-butyl-                               Example   of Example    stannyl)-1-trans-alkene                               ______________________________________                                        27        21            1-(tri-n-butylstannyl)-                                                       4-cyclopropyl-4-tri-                                                          methylsiloxy-trans-1-                                                         heptene                                               28        22            1-(tri-n-butylstannyl)-                                                       4-cyclopropyl-4-tri-                                                          methylsiloxy-trans-1-                                                         nonene                                                29        23            1-(tri-n-butylstannyl)-4-                                                     cyclopropyl-4-trimethyl-                                                      siloxy-trans-1-decene                                 30        24            1-(tri-n-butylstannyl)-4-                                                     vinyl-4-trimethylsiloxy-                                                      trans-1-heptyns                                       31        25            1-(tri-n-butylstannyl)-4-                                                     vinyl-4-trimethylsiloxy-                                                      trans-1-nonene                                        32        26            1-(tri-n-butylstannyl)-4-                                                     vinyl-4-trimethylsiloxy-                                                      trans-1-decene                                        ______________________________________                                    

EXAMPLE 33 Preparation of9-oxo-11α,16-dihydroxy-16-cyclopropyl-5-cis,13-trans-prostadienoic acid

To a stirred solution of 11.54 g of4-cyclopropyl-4-trimethylsiloxy-1-(tri-n-butylstannyl)-trans-1-octene(Example 11) in 10 ml of tetrahydrofuran at -78° C. is added 9.1 ml of2.4 M n-butyllithium in hexane during 10 minutes. The resulting solutionis stirred at -70° C. for 10 minutes, at -40° C. for 1 hour, and at -40°C. to -30° C. for 40 minutes. To the stirred solution at -78° C. isadded a solution prepared from 2.84 g of copper pentyne, 10.8 ml oftri-n-butyl-phosphine, and 25 ml of ether. The resulting solution isstirred at -78° C. for 2 hours and then treated during 10 minutes with asolution of 6.03 g of2-(6-trimethylsiloxycarbonyl-2'-cis-hexenyl-4-trimethylsiloxycyclopent-2-en-1-oneTable 6, Ref. A in 20 ml of ether. After 10 minutes the solution isstirred at -50° C. to -40° C. for 1 hour then at -40° C. to -30° C. for50 minutes. The solution is recooled to -50° C. and poured into astirred mixture of 600 ml of saturated ammonium chloride and 300 ml ofether. The organic phase is separated and washed successively withdilute hydrochloric acid, water and brine.

The residue obtained after evaporation of solvent is treated with 120 mlof gl. acetic acid, 60 ml of tetrahydrofuran, and 30 ml of water, andthe mixture is stirred at room temperature for 30 minutes, diluted with150 ml of toluene, and concentrated. The residue is purified by drycolumn chromatography on silica gel with 1% acetic acid in ethyl acetateto provide an oil, p.m.r. spectrum (acetone - d6): δ0.26 (multiplet,cyclopropyl hydrogens) and 4.12 (quartet, CH OH).

EXAMPLE 34-49

The product 9-oxo-11α,16-dihydroxy-prostadienoic or prostenoic acids ofTable 6 below are obtained by the procedure described in Example 33. Inaccordance with the process described therein, the starting1-(tri-n-butylstannyl)-4-trimethylsiloxy-trans-1-alkenes listed in Table6 are treated with n-butyllithium to provide the correspondingtrans-1-alkenyl lithium derivative which on treatment with copperpentyne-tri-n-butylphosphine complex furnish the correspondingtrans-1-alkenylcuprates, which in turn are treated with the4-oxycyclopent-2-en-1-ones listed in the table. The resulting9-oxo-11α,16-bis(trimethylsiloxy)-prostadienoic or prostenoic acidtrimethylsilyl ester is hydrolyzed to the listed products by treatmentwith acetic acid-tetrahydrofuran-water.

                                      TABLE 6                                     __________________________________________________________________________                      Starting 1-(tri-n-butylstannyl)-                                                             Product 9-oxo-11α,16-dihy-                  Starting 4-oxy-cyclopent-                                                                  4-trimethylsiloxy-trans-1-                                                                   droxy-prostadienoic or                       Example                                                                            2-en-1-one   alkene of Example                                                                            prostenoic acid.                             __________________________________________________________________________    34   Example 126  27             9-oxo-11α,16-cyclopropyl-                                               20-nor-13-trans prosten-                                                      oic acid.                                    35   Example 126  28             9-oxo-11α,16-dihydroxy-                                                 16-cyclopropyl-20-methyl                     13-trans-prostenoic acid                                                      36   Example 126  29             9-oxo-11α-dihydroxy-                                                    16-cyclopropyl-20-ethyl-                                                      13-trans-prostenoic acid                     37   Example 126  30             9-oxo-11α,16-dihydroxy-                                                 16-vinyl-20-nor-13-trans-                                                     prostenoic acid.                             38   Example 126  31             9-oxo-11α,16-dihydroxy-16-                                              vinyl-20-methyl-13-trans-                                                     prostenoic acid.                             39   Example 126  32             9-oxo-11α,16-dihydroxy-16-                                              vinyl-20-ethyl-13-trans-                                                      prostenoic acid.                             40   Example 126  11             9-oxo-11α,16-dihydroxy-16-                                              cyclopropyl-13-trans-pros-                                                    tenoic acid.                                 41   A            27             9-oxo-11α,16-dihydroxy-16-                                              cyclopropyl-20-nor-5-cis,                                                     13-trans-prostadienoic acid                  42   A            28             9-oxo-11α,16-dihydroxy-16-                                              cyclopropyl-20-methyl-5-                                                      cis,13-trans-prostadienoic                                                    acid                                         43   A            29             9-oxo-11α,16-dihydroxy-16-                                              cyclopropyl-20-ethyl-5-cis,                                                   13-trans-prostadienoic acid                  44   A            30             9-oxo-16α,16-dihydroxy-16-                                              vinyl-20-nor-5-cis,13-                                                        trans-prostadienoic acid                     45   A            31             9-oxo-11α,16-dihydroxy-16-                                              vinyl-20-methyl-5-cis,13-                                                     trans-prostadienoic acid                     46   A            32             9-oxo-11α,16-dihydroxy-16-                                              vinyl-20-ethyl-5-cis,13-                                                      trans-prostadienoic acid                     47   A             6             9-oxo-11α,16-dihydroxy-16-                                              vinyl-5-cis,13-trans-pros-                                     (by procedure of Ex. 7)                                                                      tadienoic acid.                              48   Example 127   6             1-9-oxo-11α,16-dihydroxy-                                               16-vinyl-13-trans-pros-                                                       tenoic acid methyl ester                     49   Example 128  11             1-9-oxo-11α,16-dihydroxy-                                               16-cyclopropyl-5-cis-13-                                                      trans-prostadienoic acid                                                      methyl ester                                 49A  Example 129   6             9-oxo-11α,16-dihydroxy-16-                                              vinyl-5-cis,13-trans-2a,                                                      2b-bishomoprostadienoic                                                       acid                                         49B  Example 129  11             9-oxo-11α,16-dihydroxy-16-                                              cyclopropyl-5-cis,13-trans-                                                   2a,2b-bishomoprostadienoic                                                    acid                                         49C  Example 129A 11             9-oxo-11α,16-dihydroxy-16-                                              cyclopropyl-13-trans-3-                                                       oxa-prostenoic acid                          49D  Example 129B  6             9-oxo-11α,16-dihydroxy-16-                                              vinyl-13-trans-3-oxa-pros-                                                    tenoic acid.                                 __________________________________________________________________________     A =                                                                           4trimethylsiloxy-2-(6-carbotrimethylsiloxy)-2-cis-hexenyl)-cyclopent-2-en    1-one (U.S. Pat. No. 3,873,607, Example 1125).                            

EXAMPLE 50 Preparation of9α,11α,16-trihydroxy-16-cyclopropyl-5-cis,13-trans-prostadienoic acid

To a stirred solution of 785 mg. of9-oxo-11α,16-dihydroxy-16-cyclopropyl-5-cis,13-trans-prostadienoic acid(Example 33) in 12 ml. of tetrahydrofuran at -70° is added 12 ml. of a0.5 M solution of lithium perhydro-9b-boraphenalyl hydride intetrahydrofuran. The solution is stirred at -78° C. for 30 minutes,warmed to 0° C. during 15 minutes, and treated with 0.6 ml. of water.The mixture is partitioned with ether-potassium carbonate solution. Theaqueous phase is acidified with hydrochloric acid and extracted withethyl acetate. The extract is washed with water and brine, dried overmagnesium sulfate, and concentrated. The resulting residue is subjectedto dry column chromatography on silica gel with 1% acetic acid in ethylacetate to provide a viscous oil, pmr spectrum (acetone - d₆): δ3.90(multiplet, 11β-H) and 4.10 (multiplet, 9β-H)

EXAMPLES 51-67

Reduction of the 9-oxo-derivatives listed in the Table 7 below withlithium perhydro-9 b-boraphenylalyl hydride by the method described inExample 50 provides the product 9α-hydroxy-prostadienoic and prostenoicacids of the table.

                  TABLE 7                                                         ______________________________________                                              Starting                                                                      9-oxo-prostadienoic                                                                         Product 9α,11α,16-trihydroxy-                 Ex-   or prostenoic prostadienoic or prostenoic                               ample acid of Example                                                                             acid                                                      ______________________________________                                        51    34            9α,11α,16-trihydroxy-16-cyclo-                                    propyl-20-nor-13-trans-pros-                                                  tenoic acid                                               52    35            9α,11α,16 -trihydroxy-16-cyclo-                                   propyl-20-methyl-13-trans-pros-                                               tenoic acid                                               53    36            9α,11α,16-trihydroxy-16-cyclo-                                    propyl-20-ethyl-13-trans-prosten-                                             oic acid                                                  54    37            9α,11α,16 -trihydroxy-16-vinyl-20-                                nor-13-trans-prostenoic acid                              55    38            9α,11α,16-trihydroxy-16-vinyl-20-                                 methyl-13-trans-prostenoic acid                           56    39            9α,11α, -16-trihydroxy-16-vinyl-20-                               ethyl-13-trans-prostenoic acid                            57    40            9α,11α,16-trihydroxy-16-cyclopro-                                 pyl-13-trans-prostenoic acid                              58    41            9α,11α,16-trihydroxy-16-cyclopro-                                 pyl-20-nor-5-cis,13-trans-pros-                                               tadienoic acid                                            59    42            9α,11α,16 -trihydroxy-16-cyclo-                                   propyl-20-methyl-5-cis,13-trans-                                              prostadienoic acid                                        60    43            9α,11α,16-trihydroxy-16-cyclo-                                    propyl-20-ethyl-5-cis,13-trans-                                               prostadienoic acid                                        61    44            9α,11α,16-trihydroxy-16-vinyl-                                    20-nor-5-cis,13-trans-prosta-                                                 dienoic acid                                              62    45            9α,11α,16-trihydroxy-16-vinyl-                                    20-methyl-5-cis,13-trans-                                                     prostadienoic acid                                        63    46            9α,11α,16-trihydroxy-16-vinyl-                                    20-ethyl-5-cis,13-trans-prosta-                                               dienoic acid                                              64    47            9α,11α,16-trihydroxy-16-vinyl-                                    5-cis,13-trans-prostadienoic                                                  acid                                                      65    7             9α,11α,16-trihydroxy-16-vinyl-                                    13-trans-prostenoic acid.                                 66    48            1-9α,11α,16-trihydroxy-16-vinyl-                                  13-trans-prostenoic acid methyl                                               ester                                                     67    49            1-9α,11α,16-trihydroxy-16-cyclo-                                  propyl-5-cis-13-trans-prosta-                                                 dienoic acid methyl ester                                  67A  49A           9α,11α,16-trihydroxy-16-vinyl-                                    5-cis-13-trans-2a,2b-bishomo-                                                 prostadienoic acid.                                        67B  49B           9α,11α,16-trihydroxy-16-cyclo-                                    propyl-5-cis,13-trans-2a,2b-bis-                                              homoprostadienoic acid.                                    67C  49C           9α, 11α,16-trihydroxy-16-cyclopro-                                pyl-13-trans-3-oxa-prostenoic acid                         67D  49D           9α,11α-trihydroxy-16-vinyl-                                       13-trans-3-oxa-prostenoic acid                            ______________________________________                                    

EXAMPLE 68 Preparation of9-oxo-16-hydroxy-16-vinyl-5-cis,10,13-trans-prostatrienoic acid

To a stirred solution of 0.28 g of9-oxo-11α,16-dihydroxy-16-vinyl-5-cis,13-trans-prostadienoic acid(Example 47) in 25 ml of pyridine is added 2.7 ml of acetic anhydride.After standing for 5 hours at room temperature, the solution is stirredwith a mixture of ethyl acetate and 1 M aqueous sodium bisulfate at 0°.The ethyl acetate layer is washed with brine and concentrated in thepresence of toluene.

The residue, consisting of crude9-oxo-11α-acetoxy-16-hydroxy-16-vinyl-5-cis,13-trans-prostadienoic acid,is dissolved in 20 ml of methanol with 1.2 g of potassium acetate. Afterstanding for 18 hours at room temperature, the solution is partitionedwith ethyl acetate and brine. The organic phase is washed with brine,dried over magnesium sulfate, and concentrated. The residue is purifiedby partition chromatography on Celite with the systemheptane-dichloromethane-methanol-water (80:20:15:6) to give an oil, pmrspectrum (acetone - d₆): 3.35 (multiplet, 12-H), 6.10 (quartet, 10-H),and 7.55 (quartet, 11-H).

EXAMPLES 69-83b

Treatment of the 9-oxo-11α,16-dihydroxy prostadienoic or prostenoicacids of Table 8 below with acetic anhydride in pyridine followed bypotassium acetate in methanol according to Example 68 furnishes theproduct 9-oxo-16-hydroxy-Δ¹⁰ -prostadienoic or prostatrienoic acids ofthe table.

                  TABLE 8                                                         ______________________________________                                             Starting 9-oxo-                                                               11α-16-dihydroxy                                                        prostadienoic                                                                 or prostenoic  Product 9-oxo-16-hydroxy-prosta-                          Ex.  acid of Example                                                                              dienoic or prostatrienoic acid                            ______________________________________                                        69   34             9-oxo-16-hydroxy-16-cyclopropyl-                                              20-nor-10,13-trans-prostadienoic -  acid                  70   35             9-oxo-16-hydroxy-16-cyclopropyl-                                              20-methyl-10,13-trans-prostadi-                                               enoic acid                                                71   36             9-oxo-16-hydroxy-16-cyclopropyl-                                              20-ethyl-10,13-trans-prostadi-                                                enoic acid                                                72   37             9-oxo-16-hydroxy-16-vinyl-20-nor-                                             10,13-trans-prostadienoic acid                            73   38             9-oxo-16-hydroxy-16-vinyl-20-                                                 methyl-10,13-trans-prostadien-                                                oic acid                                                  74   39             9-oxo-16-hydroxy-16-vinyl-20-                                                 ethyl-10,13-trans-prostadien-                                                 oic acid                                                  75   40             9-oxo-16-hydroxy-16-cyclopropyl-                                              10,13-trans-prostadienoic acid                            76   41             9-oxo-16-hydroxy-16-cyclopropyl-                                              20-nor-5-cis,10,13-trans-prosta-                                              trienoic acid                                             77   42             9-oxo-16-hydroxy-16-cyclopropyl-                                              20-methyl-5-cis,10,13-trans-                                                  prostatrienoic acid                                       78   43             9-oxo-16-hydroxy-16-cyclopropyl-                                              20-ethyl-5-cis,10,13-trans-                                                   prostatrienoic acid                                       79   44             9-oxo-16-hydroxy-16-vinyl-20-nor-                                             5-cis,10,13-trans-prostatrienoic                                              acid                                                      80   45             9-oxo-16-hydroxy-16-vinyl-20-meth-                                            yl-5-cis,10,13-trans-prostatrienoic                                           acid                                                      81   46             9-oxo-16-hydroxy-16-vinyl-20-ethyl-                                           5-cis,10,13-trans-prostatrienoic                                              acid                                                      82   47             9-oxo-16-hydroxy-16-vinyl-5-cis,10,                                           13-trans-prostatrienoic acid                              83   33             9-oxo-16-hydroxy-16-cyclopropyl-5-                                            cis,10,13-trans-prostatrienoic acid                       83a  49A            9-oxo-16-hydroxy-16-vinyl-5-cis,                                              10,13-trans-2a,2b-bishomoprosta-                                              trienoic acid                                             83b  49B            9-oxo-16-hydroxy-16-cyclopropyl-                                              5-cis,10,13-trans-2a,2b-bishomo-                                              prostatrienoic acid                                       83c  49C            9-oxo-16-hydroxy-16-cyclopropyl-                                              10,13-trans-3-oxa-prostadienoic                                               acid                                                      83d  49D            9-oxo-16-hydroxy-16-vinyl-10,13-                                              trans-3-oxa-prostadienoic acid                            ______________________________________                                    

EXAMPLES 84-91

Treatment of the cyclopentenone alkyl esters of Table 9 below with thecuprate derived from1-(tri-n-butylstannyl-4-cyclopropyl-4-trimethylsiloxy-trans-1-octene(Example 11) by the procedure of Example 33 or with the cuprate derivedfrom 4-trimethylsiloxy-4-vinyl-1-iodo-trans-1-octene (Example 6) by theprocedure of Example 7 followed by removal of the trimethylsilyl groupaccording to the procedure of Example 33 provides the16-substituted-16-hydroxy prostenoic alkyl esters of the Table.

                                      TABLE 9                                     __________________________________________________________________________                     Starting 1-(tri-n-butylstannyl-                                                             Product 16-substituted-16-                          Starting Cyclopentenone                                                                   4-trimethylsiloxy-trans-1-                                                                  hydroxy prostadienoic or                       Example                                                                            Alkyl Ester alkene of Example                                                                           prostenoic acid alkyl ester                    __________________________________________________________________________    84   2-(6-carbomethoxy-2-                                                                      11            methyl 9-oxo-16-hydroxy-16-                         cis-hexenyl)cyclopent-    cyclopropyl-5-cis,13-trans-                         2-en-1-one                prostadienoate                                      (U.S. Pat. No. 3,873,607)                                                85   2-(6-carbomethoxy-2-                                                                      6             methyl 9-oxo-16-hydroxy-16-                         cis-hexenyl)cyclopent-    vinyl-5-cis,13-trans-pros-                          2-en-1-one                tadienoate                                          (U.S. Pat. No. 3,873,607)                                                86   2-(6-carbethoxyhexyl)-                                                                    11            ethyl-9-oxo-16-hydroxy-16-                          2-cyclopentenone          cyclopropyl-13-trans-pros-                          (U.S. Pat. No. 3,873,607) tenoate                                        87   2-(6-carbethoxyhexyl)                                                                     6             ethyl 9-oxo-16-hydroxy-16-                          2-cyclopentenone          vinyl-13-trans-prostenoate                          (U.S. Pat. No. 3,873,607)                                                88   2-(6-carbethoxy-5-                                                                        6             ethyl 9-oxo-16-hydroxy-16-                          thiahexyl)-2-cyclo-       vinyl-3-thia-13-trans-                              pentenone                 prostenoate                                         (U.S. Pat. No. 3,873,607)                                                89   2-(6-carbethoxy-5-                                                                        11            ethyl 9-oxo-16-hydroxy-16-                          thiahexyl)-2-cyclo-       cyclopropyl-3-thia-13-trans-                        pentenone                 prostenoate                                         (U.S. Pat. No. 3,873,607)                                                90   2-(6-carbethoxy-5-                                                                        6             ethyl 9-oxo-16-hydroxy-16-                          oxahexyl)-2-cyclo-        vinyl-3-oxa-13-trans-pros-                          pentenone                 tenoate                                             (U.S. Pat. No. -91                                                                        2-(6-carbethoxy-5-                                                                          11 ethyl 9-oxo-16-hydroxy-16-                       oxahexyl)-2-cyclo-        cyclopropyl-3-oxa-13-trans-                         pentenone                 prostenoate                                         (U.S. Pat. No. 3,873,607)                                                __________________________________________________________________________

EXAMPLES 92-99

Saponification of the 16-substituted-16-hydroxy prostenoic acid alkylesters of Table 10 below with 0.5 N potassium hydroxide in 10:1 methanolwater at room temperature for 24 hours followed by acidification andether extraction provides the 16-substituted-16-hydroxy prostadienoic orprostenoic acids of the Table.

                  TABLE 10                                                        ______________________________________                                             Starting                                                                      Prostadienoic or                                                              Prostenoic acid alkyl                                                                        Product Prostadienoic or Pros-                            Ex.  esters of Example                                                                            tenoic acid                                               ______________________________________                                        92   84             9-oxo-16-hydroxy-16-cyclopropyl-                                              5-cis-13-trans-prostadienoic acid                         93   85             9-oxo-16-hydroxy-16-vinyl-5-cis,                                              13-trans-prostadienoic acid                               94   86             9-oxo-16-hydroxy-16-cyclopropyl-                                              13-trans-prostenoic acid                                  95   87             9-oxo-16-hydroxy-16-vinyl-13-trans-                                           prostadienoic acid                                        96   88             9-oxo-16-hydroxy-16-vinyl-3-thia-                                             13-trans-prostenoic acid                                  97   89             9-oxo-16-hydroxy-16-cyclopropyl-                                              3-thia-13-trans-prostenoic acid                           98   90             9-oxo-16-hydroxy-16-vinyl-3-oxa-                                              13-trans-prostenoic acid                                  99   91             9-oxo-16-hydroxy-16-cyclopropyl-                                              3-oxa-13-trans-prostenoic acid                            ______________________________________                                    

EXAMPLE 100 Preparation and separation of9α,11α,16-trihydroxy-16-cyclopropyl-5-cis-13-trans-prostadienoic acidand 9β,11α,16-trihydroxy-16-cyclopropyl-5-cis-13-trans-prostadienoicacid

To a stirred, ice-cold solution of 360 mg of9-oxo-11α,16-dihydroxy-16-cyclopropyl-5-cis,13-trans-prostadienoic acid(Example 33) in 50 ml of ethanol is added 408 mg of sodium borohydridein small portions during 1 minute. The mixture is stirred at 0° for 5minutes and at ambient temperature for 1.5 hours. The bulk of theethanol is evaporated at room temperature, and the residue ispartitioned with cold dilute hydrochloric acid and ethyl acetate. Theorganic phase is separated and washed with water and brine, dried overmagnesium sulfate and concentrated. The residue is subjected tochromatography on silica gel to give (first eluted) an oil,9β,11α,16-trihydroxy-16-cyclopropyl-5-cis,13-trans-prostadienoic acid,pmr (acetone - d₆): δ3.6(multiplet, 16-H) and 3.95 (multiplet, 9α-H and11β-H) and (second eluted) an oil,9α,11α,16-trihydroxy-16-cyclopropyl-5-cis,13-trans-prostadienoic acid,pmr spectum (acetone - d₆):δ3.90(multiplet, 11β -H) and 4.10 (multiplet,9β-H).

EXAMPLES 101-119

Treatment of the 9-oxo-prostaglandins of Table 11 below with sodiumborohydride by the procedure of Example 100 followed by chromatographyis productive of the 9α-hydroxy and 9β-hydroxy prostaglandins of thetable.

                  TABLE 11                                                        ______________________________________                                             Starting 9-oxo-                                                               prostadienoic or                                                                            Product 9α/β,11α,16-trihydroxy-                prostenoic acid                                                                             prostadienoic or prostenoic                                Ex.  of Example    acid                                                       ______________________________________                                        101  34            9α/β,11α,16-trihydroxy-16-cyclo-                             propyl-20-nor-13-trans-pros-                                                  tenoic acid                                                102  35            9α/β,11α,16 -trihydroxy-16-cyclo-                            propyl-20-methyl-13-trans-pros-                                               tenoic acid                                                103  36            9α/β,11α,16-trihydroxy-16-cyclo-                             propyl-20-ethyl-13-trans-prosten-                                             oic acid                                                   104  37            9α/β,11α,16-trihydroxy-16-vinyl-20-                          nor-13-trans-prostenoic acid                               105  38            9α/β,11α,16-trihydroxy-16-vinyl-20-                          methyl-13-trans-prostenoic acid                            106  39            9α/β,11α,16-trihydroxy-16-vinyl-20-                          ethyl-13-trans-prostenoic acid                             107  40            9α/β,11α,16-trihydroxy-16-cyclopro-                          pyl-13-trans-prostenoic acid                               108  41            9α/β,11α,16-trihydroxy-16-cyclopro-                          pyl-20-nor-5-cis,13-trans-pros-                                               tadienoic acid                                             109  42            9α/β,11α,16-trihydroxy-16-cyclo-                             propyl-20-methyl-5-cis,13-trans-                                              prostadienoic acid                                         110  43            9α/β,11α,16-trihydroxy-16-cyclo-                             propyl-20-ethyl-5-cis,13-trans-                                               prostadienoic acid                                         111  44            9α/β,11α,16-trihydroxy-16-vinyl-                             20-nor-5-cis,13-trans-prosta-                                                 dienoic acid                                               112  45            9α/β,11α,16-trihydroxy-16-vinyl-                             20-methyl-5-cis,13-trans-                                                     prostadienoic acid                                         113  46            9α/β,11α,16-trihydroxy-16-vinyl-                             20-ethyl-5-cis,13-trans-prosta-                                               dienoic acid                                               114  47            9α/β,11α,16-trihydroxy-16-vinyl-                             5-cis,13-trans-prostadienoic                                                  acid                                                       115  7             9α/β,11α,16-trihydroxy-16-vinyl-                             13-trans-prostenoic acid.                                  116  48            1-9α/β,11α,16-trihydroxy-16-vinyl-                           13-trans-prostenoic acid methyl                                               ester                                                      117  49            1-9α/β,11α,16-trihydroxy-16-cyclo-                           propyl-5-cis-13-trans-prosta-                                                 dienoic acid methyl ester                                   117a                                                                              49A           9α/β,11α,16-trihydroxy-16-vinyl-                             5-cis-13-trans-2a,2b-bishomo-                                                 prostadienoic acid.                                         117b                                                                              49B           9α/β,11α,16-trihydroxy-16-cyclo-                             propyl-5-cis,13-trans-2a,2b-bis-                                              homoprostadienoic acid.                                    118  92            9α/β,16-dihydroxy-16-cyclo-                                        propyl-5-cis-13-trans-prostadien-                                             oic acid                                                   119  93            9α/β,16-dihydroxy-16-vinyl-                                        5-cis-13-trans-prostadienoic                                                  acid                                                        119A                                                                              97            9α/β,16-dihydroxy-16-cyclopropyl-                                  13-trans-3-thiaprostenoic acid                              119B                                                                              98            9α/β,16-dihydroxy-16-vinyl-13-                                     trans-3-oxaprostenoic acid                                 ______________________________________                                    

EXAMPLES 120-125

Treatment of the prostadienoic or prostenoic acids listed in Table 12below with the indicated diazoalkane in the following manner providesthe product prostadienoate or prostenoate esters of the Table.

An ethereal solution containing a molar excess of diazoalkane is addedto a solution of the carboxylic acid in ether or ether-acetone. After 10to 30 minutes the solution is carefully evaporated and the residualester is purified in the usual way by chromatography on silica gel.

                  TABLE 12                                                        ______________________________________                                                      Starting                                                                      Prostadien-                                                                   oic or                                                                        Prostenoic                                                           Diazo-   Acid of   Product Prostadienote or                              Ex.  alkane   Example   Prostenoate Ester                                     ______________________________________                                        120  methane  33        methyl 9-oxo-11α,16-dihydroxy-                                          16-cyclopropyl-5-cis,13-trans-                                                Prostadienoate                                        121  diazo-   47        ethyl 9-oxo-11α,16-dihydroxy-                        ethane             16-vinyl-5-cis,13-trans-pros-                                                 tadienoate                                            122  1-diazo- 40        n-butyl 9-oxo-11α,16-dihydroxy-                      butane             16-cyclopropyl-13-trans-pros-                                                 tenoate                                               123  1-diazo- 7         n-decyl 9-oxo-11α,16-dihydroxy-                      decane             16-vinyl-13-trans-prostenoate                         124  1-diazo- 36        hexyl 9-oxo-11α,16-dihydroxy-16-                     hexane             cyclopropyl-20-ethyl-13-trans-                                                prostenoate                                           125  1-diazo- 39        octyl 9-oxo-11α,16-dihydroxy-16-                     octane             vinyl-20-ethyl-13-trans-pros-                                                 tenoate                                               ______________________________________                                    

EXAMPLES 126-129

Treatment of the carboxy-cyclopentenones or carbomethoxy-cyclopentenonesof Table 13 with chlorotrimethylsilane by the procedure described inU.S. Pat. No. 3,873,607 (Example 958) is productive of thebistrimethylsilylether esters or trimethylsilylether methyl esters ofthe Table.

                                      TABLE 13                                    __________________________________________________________________________    Example                                                                            Starting Cyclopentenone                                                                      Product ether                                             __________________________________________________________________________    126  2-(6-carboxyhexyl)-4-hydroxy-                                                                4-trimethylsiloxy-2-(6-carbotri-                               cyclopent-2-en-1-one.sup.1                                                                   methylsiloxyhexyl)-cyclopent-2-en-                                            1-one                                                     127  1-2-(6-carbomethoxyhexyl)-4-                                                                 1-4-trimethylsiloxy-2-(6-carbometh-                            hydroxycyclopent-2-en-1-one                                                                  oxy)-cyclopent-2-en-1-one                                 128  1-2-(6-carbomethoxy-2-cis-                                                                   1-4-trimethylsiloxy-2-(6-carbometh-                            hexenyl)-4-hydroxycyclo-                                                                     oxy-2-cis-hexenyl)cyclopent-2-en-                              pent-2-en-1-one.sup.3                                                                        1-one                                                     129  2-(6-carboxy-2-cisoctenyl)-4-                                                                2-(6-carbotrimethysiloxy-2-cis-                                hydroxycyclopent-2-en-1-one.sup.4                                                            octenyl)-4-trimethylsiloxy-                                                   cyclopent-2-en-1-one                                      129A 2-(6-carboxy-5-oxahexyl)-4-                                                                  4-trimethylsiloxy-2-(6-carbotrimeth-                           hydroxycyclopent-2-en-1-one.sup.4                                                            siloxy-5-oxahexyl)-cyclopent-2-en-                                            1-one                                                     __________________________________________________________________________     References:                                                                   .sup.1 U.S. Pat. No. 3,873,607.                                               .sup.2 Pappo et al., Tetrahedron Letters, 943 (1973).                         .sup.3 Bruhn et al., Ibid., 235 (1976).                                       .sup.4 U.S. Pat. No. 3,950,406.                                          

EXAMPLES 130-131

Treatment of the 11α-hydroxyprostaglandins of Table 14 by the procedureof Pike et al., Journ. of Org. Chem., 84 3552, 1974 is productive of theΔ⁸,12 prostaglandins of the Table.

                  TABLE 14                                                        ______________________________________                                               Starting 11α-hydroxy                                             Example                                                                              prostaglandin Product .increment..sup.8,12 prostaglandins              ______________________________________                                        130    33             9-oxo-16-hydroxy-16-vinyl-.increment..sup.8,12                                5-cis,13-trans-prostatrienoic                                                 acid                                                    131    37             9-oxo-16-hydroxy-16-cyclopropyl                                               .increment. 8,12,13-trans-prostadienoic                                       acid.                                                   ______________________________________                                    

EXAMPLE 132 Preparation of 11-oxo-9α,16-dihydroxy-16-cyclopropyl-5-cis,13-trans-prostadienoic acid

To a stirred solution of 135 mg. of9α,11α,16-trihydroxy-16-cyclopropyl-5-cis,13-trans-prostadienoic acid(Example 50) in 25 ml. of acetone and 3 ml of acetic acid at -40° C. isadded 0.15 ml. (0.4 mmoles) of Jones Reagent. After 2 hours at -40° C.to -35° C. a few drops of isopropanol are added, and the resultingmixture is partitioned with water and ether. The ether extract is washedwith water and brine, dried over magnesium sulfate, and concentratedwith the oil of toluene. The residue is purified by columnchromatography on silica gel with hexane progressively enriched in ethylacetate to provide an oil, pmr spectum (acetone - d₆): δ 2.71 (quartet,10--H's) and 4.44 (triplet, 9--H).

EXAMPLES 133-151

The 11-oxo-9α,16-dihydroxy-prostadienoic or prostenoic acids of Table 15below are prepared by oxidation of the precursor9α,11α,16-trihydroxy-precursors with Jones Reagent by the procedure ofExample 132.

                                      TABLE 15                                    __________________________________________________________________________         Starting 9α,11α,16-trihydroxy-                                                   Product 11-oxo-9α,16-dihydroxy-                          prostadienoic or prostenoic                                                                  prostadienoic or prostenoic                               Example                                                                            acid of Example                                                                              acid                                                      __________________________________________________________________________    133  51             11-oxo-9α,16-dihydroxy-16-cyclo-                                        propyl-20-nor-13-trans-prosten-                                               oic acid                                                  134  52             11-oxo-9α,16-dihydroxy-16-cyclo-                                        propyl-zo-mwrhyl-13-trans-pros-                                               tenoic acid                                               135  53             11-oxo-9α,16-dihydroxy-16-cyclo-                                        propyl-20-ethyl-13-trans-prosten-                                             oic acid                                                  136  54             11-oxo-9α,16-dihydroxy-16-vinyl-                                        20-nor-13-trans-prostenoic acid                           137  55             11-oxo-9α,16-dihydroxy-16-vinyl-                                        20-methyl-13-trans-prostenoic                                                 acid                                                      138  56             11-oxo-9α,16-dihydroxy-16-vinyl-                                        20-ethyl-13-trans-prostenoic                                                  acid                                                      139  57             11-oxo-9α,16-dihydroxy-16-cyclo-                                        propyl-13-trans-prostenoic acid                           __________________________________________________________________________         Starting 9α,11α,16                                                               Product 11-oxo-9α,16-dihydroxy-                          prostadienoic or prostenoic                                                                  prostadienoic or prostenoic                               Example                                                                            acid of Example                                                                              acid                                                      __________________________________________________________________________    140  58             11-oxo-9α,16-dihydroxy-16-cyclo-                                        propyl-20-nor-5-cis,13-trans-                                                 prostadienoic acid                                        141  59             11-oxo-9α,16-dihydroxy-16-cyclo-                                        propyl-20-methyl-5-cis,13-trans-                                              prostadienoic acid                                        142  60             11-oxo-9α-  propyl-20-methyl-13-trans-pros-                             propyl-20-ethyl-5-cis,13-trans-                                               prostadienoic acid                                        143  61             11-oxo-9α,16-dihydroxy-16-vinyl-                                        20-nor-5-cis,13-trans-prosta-                                                 dienoic acid                                              144  62             11-oxo-9α,16-dihydroxy-16-vinyl-                                        20-methyl-5-cis,13-trans-pros-                                                tadienoic acid                                            145  63             11-oxo-9α,16-dihydroxy-16-vinyl-                                        20-ethyl-5-cis,13-trans-prosta-                                               dienoic acid                                              146  64             11-oxo-9α,16-dihydroxy-16-vinyl-                                        5-cis,13-trans-prostadienoic                                                  acid                                                      __________________________________________________________________________         Starting 9α,11α,16-trihydroxy-                                                   Product 11-oxo-9α,16-dihydroxy-                          prostadienoic or prostenoic                                                                  prostadienoic or prostenoic                               Example                                                                            acid of Example                                                                              acid                                                      __________________________________________________________________________    147  65             11-oxo-9α,16-dihydroxy-16-vinyl-                                        13-trans-prostenoic acid                                  148  66             1-11-oxo-9α,16-dihydroxy-16-                                            vinyl-13-trans-prostenoic acid                            149  67             1-11-oxo-9α,16-dihydroxy-16-                                            cyclopropyl-5-cis-13-trans-                                                   prostadienoic acid methyl ester                           150  67A            11-oxo-9α,16-dihydroxy-16-vinyl-                                        5-cis,13-trans-2a,2b-bishomo-                                                 prostadienoic acid                                        151  67B            11-oxo-9α,16-dihydroxy-16-cyclo-                                        propyl-5-cis,13-trans-2a,2b-bis-                                              homoprostadienoic acid                                    152  67C            11-oxo-9α,16-dihydroxy-16-cyclo-                                        propyl-13-trans-prostenoic acid                           153  67D            11-oxo-9α,16-dihydroxy-16-vinyl-                                        13-trans-prostenoic acid                                  __________________________________________________________________________

The compounds of this invention are useful as bronchodilators for thetreatment of asthma and chronic bronchitis. Bronchodilator activity isdetermined in guinea pigs against bronchospasms elicited by intravenousinjections of 5-hydroxytryptamine, histamine or acetylcholine by theKonzett procedure. [See J. Lulling, P. Lievens, F. El Sayed and J.Prignot, Arzneimittel-Forschung, 18, 955 (1968).]

In Table 16 which follows bronchodilator activity for representativecompounds of this invention against one or more of three spasmogenicagents is expressed as an ED₅₀ determined from the results obtained withthree logarithmic cummulative intravenous doses. In this assay, thesecompounds of this invention provide an effect of longer duration thandoes natural l-PGE₁ or l-PGE₂.

                  TABLE 16                                                        ______________________________________                                        Bronchodilator Activity (Konzett Assays)                                                        ED.sub.50, mg./kg.                                                           Spasmogenic Agent                                                               5-hydroxy-                                                                              hista-  Acetyl-                                  COMPOUND           tryptamine                                                                              mine    choline                                  ______________________________________                                        9-oxo-11α,16 -dihydroxy-16-vinyl-                                       13-trans-prostenoic acid                                                                         0.00186   0.00111 0.760                                    ______________________________________                                    

A suitable class of compounds are the optically active compounds of theformula ##STR26## or a racemic mixture of that formula and the mirrorimage thereof wherein R is selected from the group consisting ofhydrogen, methyl and ethyl, R₁ is selected from the group consisting ofvinyl and cyclopropyl and n is from 3 to 5, and the pharmacologicallyacceptable cationic salts thereof when R₁ is hydrogen, such as:dl-Methyl-9-oxo-11α,16-dihydroxy-16-vinyl-5-cis-13-trans-prostadienoate;l-Methyl-9-oxo-11α,16-dihydroxy-16-vinyl-5-cis-13-trans-prostadienoate;dl-Methyl-9-oxo-11α,16-dihydroxy-16-vinyl-20-ethyl-5-cis-13-trans-prostadienoate;l-Methyl-9-oxo-11α,16-dihydroxy-16-vinyl-20-ethyl-5-cis-13-trans-prostadienoate;dl-Methyl-9-oxo-11α,16-dihydroxy-16-cyclopropyl-5-cis-13-trans-prostadienoate;l-Methyl-9-oxo-11α,16-dihydroxy-16-cyclopropyl-5-cis-13-trans-prostadienoate;dl-Methyl-9-oxo-11α,16-dihydroxy-16-cyclopropyl-20-ethyl-5-cis-13-trans-prostadienoate;andl-Methyl-9-oxo-11α,16-dihydroxy-16-cyclopropyl-20-ethyl-5-cis-13-trans-prostadienoate.

We claim:
 1. An optically active compound of the formula ##STR27## or aracemic mixture of that formula and the mirror image thereof wherein Ris selected from the group consisting of hydrogen, methy and ethyl, R₁is selected from the group consisting of vinyl and cyclopropyl and n isfrom 3 to 5, and the pharmacologically acceptable cationic salts thereofwhen R₁ is hydrogen.
 2. The compound of claim 1 wherein R₁ is vinyl. 3.The compound of claim 2 wherein n is
 3. 4.dl-Methyl-9-oxo-11α,16-dihydroxy-16-vinyl-5-cis-13-trans-prostadienoate.5.l-Methyl-9-oxo-11α,16-dihydroxy-16-vinyl-5-cis-13-trans-prostadienoate.6.dl-Methyl-9-oxo-11α,16-dihydroxy-16-vinyl-20-ethyl-5-cis-13-trans-prostadienoate.7.l-Methyl-9-oxo-11α,16-dihydroxy-16-vinyl-20-ethyl-5-cis-13-trans-prostadienoate.8.dl-Methyl-9-oxo-11α,16-dihydroxy-16-cyclopropyl-5-cis-13-trans-prostadienoate.9.l-Methyl-9-oxo-11α,16-dihydroxy-16-cyclopropyl-5-cis-13-trans-prostadienoate.10.dl-Methyl-9-oxo-11α,16-dihydroxy-16-cyclopropyl-20-ethyl-5-cis-13-trans-prostadienoate.11.l-Methyl-9-oxo-11α,16-dihydroxy-16-cyclopropyl-20-ethyl-5-cis-13-trans-prostadienoate.